Post on 24-Dec-2015
Acute and Maintenance Treatment of Bipolar
Depression
Terence A. Ketter, M.D. Terence A. Ketter, M.D.
Teaching PointsTeaching Points
Mood stabilizers are foundational agents and should be considered first line treatments, with the strongest evidence supporting the use of lithium and lamotrigine.
Emerging data suggest atypical antipsychotics provide benefit in acute bipolar depression, with the strongest evidence supporting the use of quetiapine monotherapy and the olanzapine plus fluoxetine combination.
The utility of adjunctive antidepressants in bipolar depression is controversial, as these agents can yield switching into mania or hypomania in some patients.
Pre-Lecture ExamPre-Lecture ExamQuestion 1Question 1
1. The most pervasive symptoms in bipolar disorder are those of: (choose one)
A. Mania, hypomania
B. Hypomania
C. Depression
D. Mixed States
E. None of the above
Question 2Question 2
Which of the treatments below is the LEAST appropriate strategy in bipolar depression: (choose one)
A. Mood stabilizer without antidepressant
B. Mood stabilizer with antidepressant
C. Atypical antipsychotic with antidepressant
D. Antidepressant with neither mood stabilizer nor atypical antipsychotic
Question 3Question 3
Which antidepressant option carries the greatest risk of hypomania/mania: (choose one)
A. Tricyclic antidepressants (TCAs)
B. Selective serotonin reuptake inhibitors (SSRIs)
C. Mirtazepine
D. Bupropion
Question 4Question 4
Which of the following treatments do NOT have controlled data suggesting utility in bipolar depression: (choose one)
A. Lithium
B. Lamotrigine
C. Olanzapine plus fluoxetine combination
D. Quetiapine
E. Citalopram
F. Pramipexole
Question 5Question 5
Which of the following statements best describes the role of maintenance adjunctive antidepressants in patients with bipolar disorder: (choose one)
A. Long-term adjunctive antidepressants are always beneficial.
B. Long-term adjunctive antidepressants are never beneficial.
C. Long-term adjunctive antidepressants are beneficial in most patients.
D. Long-term adjunctive antidepressants may be beneficial in some patients.
Overview
Treatment options
– Mood stabilizers
– Atypical antipsychotics
– Adjunctive antidepressants
– Alternative treatments
Treatment of acute bipolar depression
Prevention of bipolar depression
Bipolar disorders symptoms Bipolar disorders symptoms are chronic and predominantly depressiveare chronic and predominantly depressive
Judd et al 2002
53%32%
9%6%
Asymptomatic
Depressed
Hypomanic
Cycling / mixed
% of Weeks
146 Bipolar I Patients146 Bipolar I Patientsfollowed 12.8 yrsfollowed 12.8 yrs
86 Bipolar II Patients86 Bipolar II Patientsfollowed 13.4 yrsfollowed 13.4 yrs
46%50%
1% 2%
Judd et al 2003
Treatment Options in Bipolar DepressionTreatment Options in Bipolar Depression
Alternative Treatments
Pramipexole
Gabapentin
Omega-3 fatty acids
Phototherapy
Psychotherapy
Sleep deprivation
Thyroid hormones
Mood Stabilizers
Lithium
Lamotrigine
Carbamazepine
Divalproex
ECT
Atypical Antipsychotics
Quetiapine
Olanzapine
Jefferson JW, Greist JH. Textbook of Psychiatry, Washington, DC, American Psychiatric Press, 1994; Post RM, et al. Neuropsychopharmacology 1998; Worthington JJ III, Pollack MH. Am J Psychiatry 1996; Amsterdam J. J Clin Psychopharmacol 1998; Barbini B, et al. Psychiatry Res 1998; Wirz-Justice A, et al. Biol Psychiatry 1999; Stoll AL, et al. Arch Gen Psychiatry 1999; Bowden CL. J Clin Psychiatry 1998; Tohen M, et al. Arch Gen Psychiatry 2003;60:1079-88; Calabrese JR, et al. J Clin Psychiatry 1999;60:79-88; Goldberg JF, et al. Am J Psychiatry 2004;161:564-6.
Adjunctive
Antidepressants
Fluoxetine + Olanzapine
Bupropion
SSRIs
Venlafaxine
Nefazodone
Mirtazapine
MAOIs
TCAs
Acute Treatment of Bipolar Depression
Mendels J. Am J Psychiatry 1976;133:373-81 Watanabe S, et al. Arch Gen Psychiatry 1975;32:659-6682
Lithium in Acute Bipolar Depression
Li > placebo in 5/7 studies (N=158)1
– Pooled data
19% little or no antidepressant effect
81% significant antidepressant effect
Li versus TCA studies1,2
– Some included unipolars
– TCA Li in 3 studies (N=98)1,2
28 Reports* (16,800 Patients)28 Reports* (16,800 Patients)
*19 of 28 reports (16,000 patients) recorded only actual suicides.Tondo, et al. 1997.
Lithium and Suicide Risk in Major Affective Disorder
No. ofNo. of Annual riskAnnual riskreportsreports of suicideof suicide
With lithiumWith lithium 2222 0.26 ± 0.40.26 ± 0.4
Without lithiumWithout lithium 1010 1.68 ± 1.51.68 ± 1.5 }}7 to 8-fold7 to 8-folddifferencedifferencepp<0.0001<0.0001
Suicide and Suicide Attempts with Randomized Lithium or Carbamazepine
Suicide Suicide Total Suicidal Attempts Behavior
Lithium 0 0 0
Carbamazepine 5 4 9
Thies-Flechtner et al. Pharmacopsychiatry 1994;29:103-7.
30-month prospective studyin 285 recently hospitalized patients
(175 bipolar, 110 schizoaffective)
Mood Stabilizer Choice and Suicide Events in Mood Stabilizer Choice and Suicide Events in Bipolar Disorder Patients in Two Large HMOsBipolar Disorder Patients in Two Large HMOs
Events per 1,000 pt-years
Goodwin et al. JAMA 2003;290:1467-73
Medication # of PtÕs
Outpatient Attempts
Inpatient Attempts
Completed Suicides
Lithium 11,308 9.5 4.3 0.7
Divalproex 12,358 26.8* 10.65* 1.75*
Lithium + Divalproexa
3067 25.8* 11.8* 1.60
aTreatment-resistant patients; *Sig. Diff from Lithium alone (p<.05)
Medication Outpatient attempts
Inpatient attempts
Completed Suicides
Lithium 1.0 1.0 1.0
Divalproex 1.7* 1.6* 2.6**
Divalproex + Lithiuma
2.1* 2.1* 2.6
Risk ratios of events relative to patients on lithium
(Adjusted for age, sex, year of treatment, comedications, comorbidity)
Mood Stabilizer Choice and Suicide Events in Mood Stabilizer Choice and Suicide Events in Bipolar Disorder Patients in Two Large HMOsBipolar Disorder Patients in Two Large HMOs
Goodwin et al. JAMA 2003;290:1467-73
aTreatment-resistant patients; Sig. Diff from Lithium alone (*p<.001; **p<.004)
± p < 0.1 vs PBO, LOCF
-12
-10
-8
-6
-4
-2
0
0 1 2 3 4 5 6 8
Placebo (N=22)
Divalproex 62 ug/mL (N=21)
±±
Week
Me
an
Ch
an
ge
fro
m B
ase
line
Baseline - PBO 20.5, DVPX 22.6
Sachs G, et al. 40th Ann ACNP Mtg, December 9-13, 2001, Waikaloa, HI.
8-Week Randomized Double-Blind Divalproex 8-Week Randomized Double-Blind Divalproex Monotherapy in Acute Bipolar DepressionMonotherapy in Acute Bipolar Depression
Baseline HAM-D: Placebo, 19.9; Divalproex 22.0. Last observation carried forward.Davis LL, et al. J Affective Disord 2005;85:259-66.
Baseline HAM-D: Placebo, 19.9; Divalproex 22.0. Last observation carried forward.Davis LL, et al. J Affective Disord 2005;85:259-66.
8-Week Randomized Double-Blind Divalproex 8-Week Randomized Double-Blind Divalproex Monotherapy in Acute Bipolar DepressionMonotherapy in Acute Bipolar Depression
Mea
n H
AM
-D C
hang
e F
rom
Bas
elin
e (L
OC
F)
Mea
n H
AM
-D C
hang
e F
rom
Bas
elin
e (L
OC
F)
Week0 1 2 3 4 5 6 7 8
-12
-10
-8
-6
-4
-2
0
Placebo (N = 12)
Divalproex 82 ug/mL (N = 13)
P = 0.0002
22
36
25
29
24
25
19
29
11
35
4
35
8
25
0%
10%
20%
30%
40%
50%
60%
Q T P600mg
Q T P300mg
LTG200mg
OFC L TG50mg
Li Pax L i IM I Olz
Active-Placebo Response Rate Difference
Res
po
nse
Rat
e(≥
50%
dec
reas
e in
dep
ress
ion
rat
ing
)
Summary of 4 Acute Bipolar Depression StudiesSummary of 4 Acute Bipolar Depression Studies Response Rates
Placebo Response Rate
Sachs GS. In Ketter TA (ed). Advances in the Treatment of Bipolar Disorders. Am Psychiatric Press, Inc. 2005.
22
36
Calabrese et al. J Clin Psychiatry. 1999;60:79-88.Calabrese et al. J Clin Psychiatry. 1999;60:79-88.
Last Observation Carried Forward Observed Cases
MA
DR
SM
AD
RS
Ch
an
ge
Fro
m B
ase
line
Ch
an
ge
Fro
m B
ase
line
PBO 5%
LTG 50 3%
LTG 200 8%
7-Week Randomized Double-Blind Lamotrigine 7-Week Randomized Double-Blind Lamotrigine Monotherapy in Acute Bipolar I DepressionMonotherapy in Acute Bipolar I Depression
LTG 50 mg/d (n = 64)LTG 50 mg/d (n = 64)
LTG 200 mg/d (n = 63)LTG 200 mg/d (n = 63)
Placebo (n = 65)Placebo (n = 65)
WeekWeek
0
-5
-10
-15
-20
0 1 2 3 4 5 6 7
±±
±±**
******
WeekWeek
0
-5
-10
-15
-20
0 1 2 3 4 5 6 7
††
**** ** **
**** **
**
LTG 50 mg/dLTG 50 mg/d
LTG 200 mg/dLTG 200 mg/d
PlaceboPlacebo
Switch RatesSwitch Rates
±± P<0.1; P<0.1; †† * P<0.05. * P<0.05.
16-Week Randomized Open Adjunctive Therapy of 16-Week Randomized Open Adjunctive Therapy of Treatment Resistant Bipolar DepressionTreatment Resistant Bipolar Depression a a
Nierenberg AA, et al. Am J Psychiatry 2006;163;210-6.
138mg/d
9429mg/d
1.5mg/d
23.8%[5.8-41.8]
17.4%[2.4-32.4]
4.6%[0-14.6]
a 54% BPI, 46% BPII.
Lamotrigine 19%
Inositol 13%
Risperidone 13%
Switch RatesSwitch Rates
OLZ 9.7 mg(N = 351)
PBO (N = 355)
OLZ 7.4 mg+ FLX 39.3 mg(N = 82)
Week
0 1 2 3 4 6 8
Me
an
Ch
an
ge
in M
AD
RS
Sc
ore
s
-20
-15
-10
-5
0
*
*
**
**
†† †
Tohen M, et al. Arch Gen Psychiatry 2003;60:1079-88.Baseline MADRS 31.3 PBO, 32.6 OLZ, 30.8 OLZ+FLX.
* P < 0.05 vs OLN, OLN+FLX. † P < 0.05 vs OLN.
8-Week Randomized Double-Blind Olanzapine ± 8-Week Randomized Double-Blind Olanzapine ± Fluoxetine in Acute Bipolar I DepressionFluoxetine in Acute Bipolar I Depression
PBO 7%
OLZ 6%
OFC 6%
Switch RatesFluoxetine monotherapy arm excluded
due to risk of mania induction.
* P < 0.05 vs OLN, OLN+FLX. † P < 0.05 vs OLN. ITT-LOCF
Responders Remitters
OFC OLN PBO OFC OLN PBO0
10
20
30
40
50
60 54%
37%
29%
Per
cen
tag
e o
f P
atie
nts
47%
31%
23%
*
†
*
†
Tohen M, et al. Arch Gen Psychiatry 2003;60:1079-88.
PBO 7%
OLZ 6%
OFC 6%
Switch Rates
8-Week Randomized Double-Blind Olanzapine ± 8-Week Randomized Double-Blind Olanzapine ± Fluoxetine in Acute Bipolar I DepressionFluoxetine in Acute Bipolar I Depression
LTG 106 mg(N = 205)
OLZ 10.7 mg+ FLX 38.3 mg(N = 205)
Brown EB, et al. J Clin Psychiatry 2006;66:1025-33.
Baseline MADRS 30.9 OFC, 31.4 LTG. *P < 0.05, ***P < 0.001 OFC vs LTG. Trade-off: 3 lbs/MADRS point.
7-Week Randomized Double-Blind Lamotrigine vs 7-Week Randomized Double-Blind Lamotrigine vs Olanzapine + Fluoxetine in Acute Bipolar I DepressionOlanzapine + Fluoxetine in Acute Bipolar I Depression
LTG 5%
OFC 4%
Switch Rates
LTG -0.3***
OFC +3.1
Weight Change (kg)
Week
Me
an
Ch
an
ge
in M
AD
RS
Sc
ore
s
0 1 2 3 4 6 7
-20
-15
-10
-5
0
-25
5
** *
*
*
Responders ≥ 7% Weight Gain
OFC LTG OFC LTG0
10
20
30
40
50
60
69%
60%
Per
cen
tag
e o
f P
atie
nts
23%
0%
±
***
70
Brown EB, et al. J Clin Psychiatry 2006;66:1025-33.
± P < 0.08, *** P < 0.001 OFC vs LTG. Trade-off: 9% response vs 23% weight gain.
LTG 5%
OFC 4%
Switch Rates
7-Week Randomized Double-Blind Lamotrigine vs 7-Week Randomized Double-Blind Lamotrigine vs Olanzapine + Fluoxetine in Acute Bipolar I DepressionOlanzapine + Fluoxetine in Acute Bipolar I Depression
-20
-15
-10
-5
0
Quetiapine 600 mg (N = 170)
Quetiapine 300 mg (N = 172)
Placebo (N = 169)
†
†
†
†
† †† †
†
†
† †
† † † †
0 1 2 43 65 7 8
Study Week
ITT, LOCF
Ch
ang
e F
rom
Bas
elin
e(L
S M
ean
s)
Baseline MADRS 30.3 PBO, 30.4 QTP 300, 30.6 QTP 600.
†P<0.001 (quetiapine vs placebo)
8-Week Randomized Double-Blind Quetiapine 8-Week Randomized Double-Blind Quetiapine Monotherapy in Acute Bipolar DepressionMonotherapy in Acute Bipolar Depression
Calabrese JR, et al. Am J Psychiatry 2005;162:1351-60.
PBO 4%
QTP 300 4%
QTP 600 2%
Switch Rates
ITT, LOCFBaseline MADRS 29.6 PBO, 31.1 QTP 300, 29.9 QTP 600.
*P<0.01, †P<0.001 (quetiapine vs placebo).
8-Week Randomized Double-Blind Quetiapine 8-Week Randomized Double-Blind Quetiapine Monotherapy in Acute Bipolar DepressionMonotherapy in Acute Bipolar Depression
Thase ME, et al. J Clin Psychopharmacol 2006;26:600-9.
Mo
ntg
om
ery-
Asb
erg
Dep
ress
ion
Rat
ing
Sca
leIm
plr
ove
men
t
PBO 7%
QTP 300 2%
QTP 600 4%
Switch Rates
8-Week Randomized Double-Blind Quetiapine 8-Week Randomized Double-Blind Quetiapine Monotherapy in Acute Bipolar DepressionMonotherapy in Acute Bipolar Depression
Thase ME, et al. J Clin Psychopharmacol 2006;26:600-9.
BOLDER I BOLDER II
Per
cen
tag
e o
f P
atie
nts
Res
po
nd
ing
(≥ 5
0% M
AD
RS
Dec
reas
e)
PBO QTP300
QTP600
PBO0
10
20
30
40
50
60 58% 58%
36%40%
37%
24%
***
***
QTP300
QTP600
***
Response Rates
Calabrese JR, et al. Am J Psychiatry 2005;162:1351-60.
*p < 0.05, **p< 0.01, *** p < 0.001 vs placebo.
PBO 4%
QTP 300 4%
QTP 600 2% PBO 7%
QTP 300 2%
QTP 600 4%
Switch Rates
Switch Rates
Bipolar Disorder I(N=657)
Bipolar Disorder II(N=321)
†
‡
MA
DR
S L
S M
ean
C
han
ge
Fro
m B
asel
ine
Imp
rove
men
t
†p<0.01; ‡p<0.001 vs. placebo (N at baseline); ITT = intent to treat; AstraZeneca (data on file); Thase ME (2006), Presented at the 159th Annual Meeting of the APA. Toronto, Canada; May 20-25; Calabrese JE et al. (2005), Am J Psychiatry 162(7):1351-1360
BOLDER I and II: MADRS Total Score BOLDER I and II: MADRS Total Score Bipolar I vs. II DisorderBipolar I vs. II Disorder
‡
†
Quetiapine 300Quetiapine 600Placebo-20
-16
-12
-8
-4
0
Magnitudes of Effects in Controlled Trials in Magnitudes of Effects in Controlled Trials in Acute Bipolar I DepressionAcute Bipolar I Depression
1Tohen M, et al. Arch Gen Psychiatry 2003;60:1079-1088; 2Calabrese JR, et al. 157th APA Annual Meeting, May 1-6, 2004, New York, NY. Abstract NR756. Page 284; 3Calabrese JR, et al. J Clin Psychiatry 1999;60:79-88.
Effect Size
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
OLZ10 mg
OLZ7.5 mg
+FLX
40 mgQTP
300 mgQTP
600 mgLTG
50 mgLTG
200 mg
Response Rate (%)a
0
10
20
30
40
50
60
70
OLZ10 mg
OLZ7.5 mg
+FLX
40 mgQTP
300 mgQTP
600 mgLTG
50 mgLTG
200 mg
2Calabrese 2004. 3Calabrese 1999.1Tohen 2003. 2Calabrese 2004. 3Calabrese 1999.1Tohen 2003.
Effect Size (ES) = (improvement over PBO) / (pooled SD)(small <0.4; mod 0.5-0.9; large >1.0). a >50% MADRS decrease
6-week Randomized Double-Blind Adjunctive 6-week Randomized Double-Blind Adjunctive Pramipexole in Acute Bipolar DepressionPramipexole in Acute Bipolar Depression
Response RatesP
erce
nt
resp
on
der
s(≥
50%
HD
RS
/MA
DR
S d
ecre
ase)
20%(2/10)
67%(8/12)
P<0.04
Pramipexole Placebo Pramipexole Placebo0
5
10
15
20
25
30
35
40
45
50
60%(6/10)
9%(1/11)
60
P<0.02
1.7mg/d
1.7mg/d
Zarate CA, et al.Biol Psychiatry 2004; 56:54-60.
Goldberg JF, et al.Am J Psychiatry 2004; 161:564-6
7021 BPII on
Li (N=12, 0.8 mEq/L),DVPX (N=9, 73 ug/mL)
15 BPI, 7 BPII on Li (N=6, 0.7 mEq/L),
DVPX (N = 9, 81 ug/mL), LTG (N=6), GBP (N=3),CBZ (N=2)
6-week Randomized Double-Blind Adjunctive 6-week Randomized Double-Blind Adjunctive Pramipexole in Acute Bipolar DepressionPramipexole in Acute Bipolar Depression
Switch RatesP
erce
nt
wit
h H
ypo
man
ia o
r M
ania
0%(0/10)
8%(1/12 mania)
Pramipexole Placebo Pramipexole Placebo0
5
10
15
20
25
30
35
40
45
50
10%(1/10 hypomania)
18%(2/11 hypomania)
60
1.7mg/d
1.7mg/d
Zarate CA, et al.Biol Psychiatry 2004; 56:54-60.
Goldberg JF, et al.Am J Psychiatry 2004; 161:564-6
7021 BPII on
Li (N=12, 0.8 mEq/L),DVPX (N=9, 73 ug/mL)
15 BPI, 7 BPII on Li (N=6, 0.7 mEq/L),
DVPX (N = 9, 81 ug/mL), LTG (N=6), GBP (N=3),CBZ (N=2)
Response Rates
Per
cen
t R
esp
on
der
s(≥
50%
ID
S d
ecre
ase)
*p < 0.05 vs placebo.
Modafinil Placebo0
10
20
30
40
50
60
22%
44%
177 mg/dN = 41 N = 44
*
6-week Randomized Double-Blind Adjunctive 6-week Randomized Double-Blind Adjunctive Modafinil in Acute Bipolar DepressionModafinil in Acute Bipolar Depression
Frye M, et al. Am J Psychiatry 2007;164:1242-9.
Placebo 11.4%
Modafinil 4.9%
Switch Rates
Response in Randomized Controlled TrialsResponse in Randomized Controlled Trialsof Antidepressants vs. Placebo in Bipolar Depressionof Antidepressants vs. Placebo in Bipolar Depression
Gijsman et al, American Journal of Psychiatry. 2004;161:1537-1547.
Paroxetine, Imipramine, Placebo Added to Paroxetine, Imipramine, Placebo Added to Lithium in Bipolar DepressionLithium in Bipolar Depression
Nemeroff CB, et al. Am J Psychiatry. 2001;158:906-912. *p < 0.05
Li + PXT 33 mg/d (n=35) Li + IMI 167 mg/d (n=39)Li + PBO (n=43)
0
10
20
30
40
50
60
All Subjects
% R
espo
nder
s
Lithium < 0.8
*
*
Li + PBO 2%
Li + PXT 0%
Li + IMI 8%
Switch Rates
Young, et al. Am J Psychiatry 2000;157:124-6.
Adjunctive Paroxetine vs Second Mood Adjunctive Paroxetine vs Second Mood Stabilizer in Bipolar DepressionStabilizer in Bipolar Depression
Similar Efficacy*
Treatment Duration (wks)
50%
ResponseRates
64%
Ham
ilto
n D
epre
ssio
n S
cale
(17
ite
m)
Double-Blind Adjunctive
2nd Mood Stabilizer
Paroxetine
•
Baseline 1 2 3 4 5 60
5
10
15
20
25
• • • ••
•••
• • • • •
*Last Observation Carried Forward Analysis
Better Tolerability
2nd Mood Stabilizer
Dro
po
ut
Rat
e (
%)
38%(6/16)
0%(0/11)
40
20
0Paroxetine
p < 0.05
Recovery RatesP
erce
nta
ge
of
Pat
ien
ts
0
5
10
15
20
2568% BPI, 32% BPII
Bupropion - 300 mg/d (median, N = 86)Paroxetine - 30 mg/d (median, N = 93)
26-Week Double-Blind Adjunctive Antidepressant vs Placebo in Acute Bipolar Depression
30
Adding antidepressant no better or worse than adding placebo to mood stabilizer(s).
P=0.40NNT = 26
Mood Stabilizer + Antidepressant
Mood Stabilizer+ Placebo
27.3%(51/187)
23.5%(42/179)
P=0.84NNH = 167
Mood Stabilizer + Antidepressant
Mood Stabilizer+ Placebo
10.7%(20/187)10.1%
(18/179)
Switch Rates
Sachs GS, et al. N Engl J Med 2007;356:1711-22.
Miklowitz DJ, et al. Arch Gen Psychiatry 2007;64:419-27.
52-Week Adjunctive Intensive Psychosocial Intervention vs Collaborative Care in Acute Bipolar Depression
Up to 30sessions
3sessions
N = 163
N = 130p = 0.01Intensive Collaborative
Median time to 50% recovery (days) 169 [138-230] 279 [-]
Median time to 25% recovery (days) 98 [88-112] 125 [105-168]
Recovered at 1 year (%) 64.4 51.5
Miklowitz DJ, et al. Arch Gen Psychiatry 2007;64:419-27.
52-Week Adjunctive Intensive Psychosocial Intervention vs Collaborative Care in Acute Bipolar Depression
Up to 30sessions
3sessions
N = 163
N = 130p < 0.05
Miklowitz DJ, et al. Arch Gen Psychiatry 2007;64:419-27.
52-Week Adjunctive Intensive Psychosocial Intervention vs Collaborative Care in Acute Bipolar Depression
Up to 30sessions
3sessions
N = 163
N = 130
Odds of Being Well in Any MonthIntensive 1.58 x Collaborative
p = 0.003
Lewis JL, Winokur G. Arch Gen Psychiatry 19821; Prien RF, et al. Arch Gen Psychiatry 1984.
Do Antidepressants Induce Mania?
41% Natural switch rate depression to mania (on no antidepressants) 1
Switch rate on medications 2
– 53% Imipramine
– 28% Lithium plus imipramine
– 26% Lithium
Switch Rate From Index Depression Into Mania
Angst J. Psychopathology 1985.
Sw
itc
h R
ate
(%
)
1920 1930 1940 1950 1960 1970 1980
Spontaneous(N=200)
ECT(N=100)
Nano-leptics(N=100)
Tricyclics(N=509)
0
6
8
4
2
10
Year
By Era and Prevailing Treatment
Peet M. Br J Psychiatry. 1994;164:549-550.
Increased Mania Switch Rates with TricyclicsIncreased Mania Switch Rates with Tricyclics%
With
Man
ic S
witc
h
0
2
4
6
8
10
12
PBO Sertraline / Paroxetine TCAs
11.2%(14/125)
3.7%(9/242)
4.2%(2/48)
**
** p < 0.01 vs PBO
Switch Rates With Tricyclic vs.Switch Rates With Tricyclic vs.Other AntidepressantsOther Antidepressants
Gijsman et al, American Journal of Psychiatry. 2004; 161: 1537-1547
Manic Switch Rates in Randomized Controlled TrialsManic Switch Rates in Randomized Controlled Trials of Antidepressants vs. Placeboof Antidepressants vs. Placebo
Gijsman et al, American Journal of Psychiatry. 2004;161:1537-1547
P = NS.
Bupropion Sertraline Venlafaxine
49%
53%51%
Per
cen
tag
e o
f P
atie
nts
wit
hE
ith
er ≥
50%
ID
S D
ecre
ase
or
≥ 2
po
int
CG
I Im
pro
vem
ent
10-Week Randomized Adjunctive Antidepressants in Acute Bipolar Depressiona
a 73% Bipolar I, 26% Bipolar II, 1% Bipolar NOS; 82% double-blind, 12% open.
Post RM, et al. Br J Psychiatry 2006;189:124-31.
286 mg/dN = 51
192 mg/dN = 58
195 mg/dN = 65
Response Rates
0
10
20
30
40
50
60
0
10
20
30
40
P = 0.05.
YMRS >13
BUP SERT VEN
4%7%
15%
Per
cen
tag
e o
f P
atie
nts
P < 0.01.
CGI-MIncrease ≥ 2
BUP SERT VEN
10% 9%
29%P = 0.03.
YMRS >13 orCGI-M ≥ 3
BUP SERT VEN
14%16%
31%
N = 51 N = 51 N = 51N = 58 N = 58 N = 58N = 65 N = 65 N = 65
Switch Rates
10-Week Randomized Adjunctive Antidepressants in Acute Bipolar Depressiona
a 73% Bipolar I, 26% Bipolar II, 1% Bipolar NOS; 82% double-blind, 12% open.
Post RM, et al. Br J Psychiatry 2006;189:124-31.
Angst J. Psychopathology 19851; Prien RF, et al. Arch Gen Psychiatry 19732; Wehr TA, Goodwin FK. Psychopharmacol Bull 19873
Do Antidepressants Induce Rapid Cycling?
Increased rapid cycling since TCAs introduced 1
Mania rates over 2 years 2
– 67% Imipramine
– 33% Placebo
– 18% Lithium
Antidepressants induce reversible rapid cycling in
double-blind placebo-controlled studies.3
Tricyclics Shorten Cycle Length
Wehr TA, Goodwin FK. Am J Psychiatry 1987.
Tricyclic Treatment Status
Cyc
le L
eng
th (
day
s)
300
250
200
150
100
50
0
10 Bipolar Disorder Patients
Off Off OffOn On
TCAs TCAs
Acute Bipolar I Depression AlgorithmAcute Bipolar I Depression Algorithm
Optimize current mood stabilizer (if applicable) before
initiating additional treatment for depression
Patients on Li - optimize (serum Li level ≥ 0.8 mEq/L) to
determine whether adjunctive intervention necessary
Patients with recent and/or severe history of mania - receive
or add an effective antimanic agent
Stage 1
Adjunctive LTG if depression persists after mood stabilizer
optimization
Number of iterations at each level and adjunctive treatment(s) to be determined by clinician judgmentSuppes T, et al. J Clin Psychiatry 2005;66:870-86.
Acute Bipolar I Depression AlgorithmAcute Bipolar I Depression Algorithm
Stage 2: If Stage 1 ineffective or not tolerated*
QTP monotherapy or OFC
Although onset of action faster than LTG, overall efficacy and
long-term tolerability evidence favors LTG (at Stage 1)
Stage 3: If Stages 1 and 2 ineffective or not tolerated*
Combination of two agents already introduced in algorithm
Li, LTG, QTP, and OFC combination
OFC a two-drug combination, so adding another agent yields
three-drug combination
Number of iterations at each level and adjunctive treatment(s) to be determined by clinician judgmentSuppes T, et al. J Clin Psychiatry 2005;66:870-86.
Acute Bipolar I Depression AlgorithmAcute Bipolar I Depression Algorithm
Stage 4: If Stages 1, 2, and 3 ineffective or not tolerated*
ECT and combination therapy ( Li, LTG, QTP, OFC
combination, VPA or CBZ in combined with SSRI, bupropion,
or venlafaxine)
Minority opinion that Stage 4 should precede Stages 2 and 3
Stage 5: If Stages 1, 2, 3, and 4 ineffective or not tolerated*
MAO-I, other atypical antipsychotics not included,
pramipexole, new combinations of drugs included in the
algorithm, inositol, stimulants, and thyroid supplementation
Number of iterations at each level and adjunctive treatment(s) to be determined by clinician judgmentSuppes T, et al. J Clin Psychiatry 2005;66:870-86.
Maintenance Treatment of Bipolar Depression
Lithium (n=251)
Placebo (n=263)
0
20
40
60
80
100
Overall Relapse Relapse Into Depression Relapse Into Maniaor Hypomania
Pe
rce
nta
ge
of
Pa
tie
nts
23%
56%
37%
21%
81%
34%
Goodwin FK, Jamison KR: Manic-Depressive Illness, Oxford University Press, New York 1990:688-9.
Summary of Double-Blind Lithium MonotherapySummary of Double-Blind Lithium Monotherapyvs Placebo Maintenance Trials in 1970svs Placebo Maintenance Trials in 1970s
Lithium Compared to Placebo, Primarily After Manic/Mixed EpisodesLithium Compared to Placebo, Primarily After Manic/Mixed Episodes
SuperiorDepressionPrevention
SuperiorDepressionPrevention
SuperiorEpisode
Prevention
SuperiorEpisode
Prevention
SuperiorMania
Prevention
SuperiorMania
Prevention
Lithium Prevention of Any RelapseLithium Prevention of Any Relapse
in Bipolar Disorderin Bipolar Disorder
Geddes JR et al. Am J Psychiatry 2004;161:217-222.
Areas of blue boxes reflect weights of studies in meta-analysis.bLower confidence interval extends beyond graph (0.08).
Lithium Prevention of Depressive RelapseLithium Prevention of Depressive Relapse
in Bipolar Disorderin Bipolar Disorder
Geddes JR et al. Am J Psychiatry 2004;161:217-222.
Areas of blue boxes reflect weights of studies in meta-analysis.bLower confidence interval extends beyond graph (0.10).
Lithium Prevention of Manic RelapseLithium Prevention of Manic Relapse
in Bipolar Disorderin Bipolar Disorder
Geddes JR et al. Am J Psychiatry 2004;161:217-222.
Areas of blue boxes reflect weights of studies in meta-analysis.
DVP = divalproex PBO = placeboGyulai et al. Neuropsychopharmacol 2003;28:1374-82.
LI = lithiumSSRI = selective serotonin reuptake inhibitor
0%
5%
10%
15%
20%
DVP (n=187) PBO (n=94)
Per
cen
tag
e o
f P
atie
nts
D
isc
on
tin
uin
g D
ue
to
Dep
ress
ion
P = 0.017
Overall Patients Receiving SSRI Rescue
0%5%
10%15%20%25%30%35%40%45%50%
DVP + SSRI (n=41)
PBO + SSRI (n=20)
P = 0.03
Per
cen
tag
e o
f P
atie
nts
D
isc
on
tin
uin
g D
ue
to
Dep
ress
ion
12-Month Double-Blind Divalproex, Lithium 12-Month Double-Blind Divalproex, Lithium Monotherapy vs Placebo MaintenanceMonotherapy vs Placebo Maintenance
Fewer Dropouts Due to Depression with Divalproex vs Placebo After Manic/Mixed Episodes
Fewer Dropouts Due to Depression with Divalproex vs Placebo After Manic/Mixed Episodes
Goodwin GM, et al. J Clin Psychiatry 2004;65:432-41.
Lamotrigine and LithiumLamotrigine and LithiumEffective in Bipolar I Prophylaxis Effective in Bipolar I Prophylaxis
Time to Intervention for Any Episode (pooled recently manic/dep pts)Time to Intervention for Any Episode (pooled recently manic/dep pts)
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 10 20 30 40 50 60 70Week
Su
rviv
al E
sti
ma
te
Placebo (n=188)
Lamotrigine 245 mg/d (n=223)
Lithium 0.7 mEq/L (n=164)
LTG v. PBO, p < 0.001Li v. PBO, p < 0.001LTG v. Li, p = 0.629
LTG Li PBO0
10
20
30
40
50
22%
42%37%
18 Months
Patients stabilized on lamotrigine prior to randomization.
Some patients considered intervention-free for depression could have had intervention for mania.
Goodwin GM, et al. J Clin Psychiatry 2004;65:432-41.
Lamotrigine Effective inLamotrigine Effective inBipolar I Depression Prophylaxis Bipolar I Depression Prophylaxis
Time to Intervention for Depression (pooled recently manic/dep pts)Time to Intervention for Depression (pooled recently manic/dep pts)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0 10 20 30 40 50 60 70Week
Su
rviv
al E
sti
ma
te
LTG v. PBO, p = 0.009Li v. PBO, p = 0.120LTG v. Li, p = 0.325
LTG Li PBO0
10
20
30
40
50
60
41%
53%57%
18 Months
Placebo (n=188)
Lamotrigine 245 mg/d (n=223)
Lithium 0.7 mEq/L (n=164)
Patients stabilized on lamotrigine prior to randomization.
Some patients considered intervention-free for mania could have had intervention for depression.
Goodwin GM, et al. J Clin Psychiatry 2004;65:432-41.
Lamotrigine and Lithium Effective inLamotrigine and Lithium Effective inBipolar I Mania Prophylaxis Bipolar I Mania Prophylaxis
Time to Intervention for Mania (pooled recently manic/dep pts)Time to Intervention for Mania (pooled recently manic/dep pts)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0 10 20 30 40 50 60 70Week
Su
rviv
al E
sti
ma
te
LTG v. PBO, p = 0.034Li v. PBO, p < 0.001LTG v. Li, p = 0.030
Placebo (n=188)
Lamotrigine 245 mg/d (n=223)
Lithium 0.7 mEq/L (n=164)
LTG Li PBO0
20
40
60
80
53%
80%
65%
18 Months
Patients stabilized on lamotrigine prior to randomization.
Incidence of Mania/Hypomania/Mixed Incidence of Mania/Hypomania/Mixed Episodes Reported as Adverse EventsEpisodes Reported as Adverse Events
Combined AnalysisCombined Analysis
0
5
10
15
20
25
Lamotrigine (n=227)
Lithium (n=166)
Placebo (n=190)
Per
cen
t o
f p
atie
nts
In all bipolar controlled trials, adverse events of mania were reported as 5% lamotrigine, 3% lithium, and 4% placebo.
Goodwin GM, et al. J Clin Psychiatry 2004;65:432-41.
Patients stabilized on lamotrigine prior to randomization.
5% 4%
7%
Olanzapine 12.5 mg/d (n=225)
Placebo (n=136)
0
20
40
60
80
100
Overall Relapse Relapse Into Depression Relapse Into Mania
Pe
rce
nta
ge
of
Pa
tie
nts
p<.001
p=.015
p<.001
16.4%
41.2%47.8%
34.7%
80.1%
46.7%
Stabilized on OLZ before randomization. Relapse criteria - hospitalized or YMRS or HAMD-21 >= 15. Tohen MF, et al. Am J Psychiatry 2006;163:247-56.
12-Month Double-Blind Olanzapine 12-Month Double-Blind Olanzapine Monotherapy vs Placebo MaintenanceMonotherapy vs Placebo Maintenance
Olanzapine Compared to Placebo After Manic/Mixed EpisodesOlanzapine Compared to Placebo After Manic/Mixed Episodes
SuperiorDepressionPrevention
SuperiorDepressionPrevention
SuperiorEpisode
Prevention
SuperiorEpisode
Prevention
SuperiorMania
Prevention
SuperiorMania
Prevention
Pe
rce
nta
ge
of
Pa
tie
nts
Stabilized on OLZ+Li before randomization. Relapse criteria - YMRS or HAMD-21 >= 15. Tohen MF, et al. Am J Psychiatry 2005;162:1281-90.
0
10
20
30
40
50
14.3%
28.0%
p=.055
p=.895p<.001
Overall Relapse Relapse Into Depression Relapse Into Mania
15.4%16.1%
38.8%
30.0%
Olanzapine 11.9 mg/d (n=217)
Lithium 1103 mg/d (0.77 mEq/L) (n=214)
12-Month Double-Blind Olanzapine vs 12-Month Double-Blind Olanzapine vs Lithium Maintenance MonotherapyLithium Maintenance Monotherapy
EquivalentDepressionPrevention
EquivalentDepressionPrevention
Olanzapine Compared to Lithium After Manic/Mixed EpisodesOlanzapine Compared to Lithium After Manic/Mixed Episodes
EquivalentEpisode
Prevention
EquivalentEpisode
Prevention
SuperiorMania
Prevention
SuperiorMania
Prevention
0
10
20
30
13%12%
6%5%Pe
rce
nt
of
Pa
tien
ts
43%
25% 23%
8%
Relapse intoMania
40
50
Relapse intoMixed
Relapse intoDepression
OverallRelapse
Aripiprazole 24.3 mg/d (n=77)
Placebo (n=83)
p=.013
p=.009
EquivalentDepressionPrevention
EquivalentDepressionPrevention
SuperiorEpisode
Prevention
SuperiorEpisode
Prevention
EquivalentMixed
Prevention
EquivalentMixed
Prevention
SuperiorMania
Prevention
SuperiorMania
Prevention
Stabilized on ARI before randomization.Keck PE, et al. 157th APA Annual Meeting; May 1-6, 2004; New York, NY. Abstract NR746.
26-Week Double-Blind Aripiprazole vs Placebo 26-Week Double-Blind Aripiprazole vs Placebo Continuation/Maintenance MonotherapyContinuation/Maintenance Monotherapy
Aripiprazole Compared to Placebo After Manic/Mixed EpisodesAripiprazole Compared to Placebo After Manic/Mixed Episodes
Antidepressants After Depression Resolution
Sachs G, 2000. Personal communication.
Disorder / Episode Pattern Begin Taper Comments
Unipolar 6–12 months Maintenance if
≥ 3 episodes
Bipolar
Monophasic 6–12 weeks Repeat if relapse
Biphasic - MDE Maintenance if
repeated relapses
Bipolar
Biphasic - DME 6–12 days Start taper after
Polyphasic first euthymic visit
Hx rapid cycling
Hx iatrogenic mania
Controlled Maintenance Studies of Controlled Maintenance Studies of Antidepressants for Bipolar DepressionAntidepressants for Bipolar Depression
Study N, Duration Efficacy Switch
Prien et al ’73 N=44, 24 mo Li > IMI = PBO
Wehr & Goodwin ‘79
N=5, 27 mo Li = Li + DMI Li + DMI >> Li
Quitkin et al ‘81 N=75, 19 mo Li = Li + IMI Li + IMI > Li
Kane et al ‘82 N=22, 11 mo Li > PBO = IMI
Prien et al ‘84 N=117, 30 mo Li = Li + IMI> IMI IMI > Li + IMI = Li
Sachs et al ‘94 N=15, 12 mo Li + BUP= Li + DMI
Li + DMI > Li + BUP
Kane et al Arch Gen Psychiatry 1982;39:1065-9; Prien et al Arch Gen Psychiatry 1984;41:1096-1104; Prien et al Arch Gen Psychiatry Kane et al Arch Gen Psychiatry 1982;39:1065-9; Prien et al Arch Gen Psychiatry 1984;41:1096-1104; Prien et al Arch Gen Psychiatry 1973;29:420-5; Quitkin et al Arch Gen Psychiatry 1981;38:902-7; Sachs et al J Clin Psychiatry 1994;55:391-3; Wehr & Goodwin Arch 1973;29:420-5; Quitkin et al Arch Gen Psychiatry 1981;38:902-7; Sachs et al J Clin Psychiatry 1994;55:391-3; Wehr & Goodwin Arch Gen Psychiatry 1979;36:555-9.Gen Psychiatry 1979;36:555-9.
Bipolar Versus Unipolar Bipolar Versus Unipolar Maintenance Treatment DissociationMaintenance Treatment Dissociation
Adapted from Prien et al Arch Gen Psychiatry 1984;41:1096:1104.Li 0.8 mEq/L; IMI 125 mg/d
Bipolar UnipolarIMI+LI Li IMI PBO
Cu
mu
lati
ve P
rob
abili
ty o
f R
emai
nin
g W
ell
0
10
20
30
40
50
60
70
80
90
3 6 9 12 15 18 21 23 25 27 30Months
100
Cu
mu
lati
ve P
rob
abili
ty o
f R
emai
nin
g W
ell
0
10
20
30
40
50
60
70
80
90
100
3 6 9 12 15 18 21 24 27Months
Antidepressant Continuation BeneficialAntidepressant Continuation Beneficialin Some (15%?) Patientsin Some (15%?) Patients
Prospective 1-year follow-upRemission of MDE with ADadded to mood stabilizer
Tolerated AD ≥ 2 months
Continuation: AD > 6 monthsDiscontinuation: AD < 6 months
n = 41(36% relapsed)
n = 43(70% relapsed)
Altshuler et al. Am J Psychiatry. 2003;160:1252-62.
Treatment of Bipolar Depression
Acute treatment – Lithium, lamotrigine– Olanzapine plus fluoxetine, quetiapine– Adjunctive antidepressants– Alternative treatments
Maintenance treatment
– Lithium, lamotrigine– Divalproex– Adjunctive antidepressants (controversial)– Alternative treatments
New treatment options emerging
Post-Lecture ExamPost-Lecture ExamQuestion 1Question 1
1. The most pervasive symptoms in bipolar disorder are those of: (choose one)
A. Mania, hypomania
B. Hypomania
C. Depression
D. Mixed States
E. None of the above
Question 2Question 2
Which of the treatments below is the LEAST appropriate strategy in bipolar depression: (choose one)
A. Mood stabilizer without antidepressant
B. Mood stabilizer with antidepressant
C. Atypical antipsychotic with antidepressant
D. Antidepressant with neither mood stabilizer nor atypical antipsychotic
Question 3Question 3
Which antidepressant option carries the greatest risk of hypomania/mania: (choose one)
A. Tricyclic antidepressants (TCAs)
B. Selective serotonin reuptake inhibitors (SSRIs)
C. Mirtazepine
D. Bupropion
Question 4Question 4
Which of the following treatments do NOT have controlled data suggesting utility in bipolar depression: (choose one)
A. Lithium
B. Lamotrigine
C. Olanzapine plus fluoxetine combination
D. Quetiapine
E. Citalopram
F. Pramipexole
Question 5Question 5
Which of the following statements best describes the role of maintenance adjunctive antidepressants in patients with bipolar disorder: (choose one)
A. Long-term adjunctive antidepressants are always beneficial.
B. Long-term adjunctive antidepressants are never beneficial.
C. Long-term adjunctive antidepressants are beneficial in most patients.
D. Long-term adjunctive antidepressants may be beneficial in some patients.
Answers to Pre & Post Competency ExamAnswers to Pre & Post Competency Exam
1. C
2. D
3. A
4. E
5. D